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Hemangiosarcoma

Hemangiosarcoma is a rare, highly aggressive cancer that originates from endothelial cells lining blood vessels, forming malignant tumors that can rapidly metastasize to distant organs. In humans, it is often referred to as angiosarcoma and accounts for approximately 1-2% of all soft tissue sarcomas (with an incidence of about 1-2 cases per million people annually), typically presenting as high-grade malignancies with a poor prognosis. While uncommon in humans, hemangiosarcoma is one of the most prevalent cancers in dogs (accounting for 5-7% of all canine malignancies), particularly affecting older, large-breed animals such as German Shepherds, Golden Retrievers, and Labrador Retrievers, where it frequently involves the spleen or heart. In humans, angiosarcomas most commonly arise in (especially the head, , or ), , liver, or heart, and are associated with risk factors including prior , exposure to chemicals like , chronic (as in Stewart-Treves syndrome), and certain genetic conditions such as type 1. Symptoms often include bruise-like lesions on that may ulcerate, painless swelling, or organ-specific effects like or depending on the site; early detection is challenging due to its nonspecific presentation and aggressive nature, leading to a 5-year of around 35% even with . Diagnosis typically involves with immunohistochemical staining for markers like and , supported by such as or MRI to assess spread. In dogs, hemangiosarcoma is characterized by its tendency to cause upon tumor rupture, resulting in sudden collapse, pale gums, rapid breathing, or even death; subcutaneous forms may appear as red or bruised masses on the skin. The disease is diagnosed through abdominal , chest X-rays, or cytology of fluid from effusions, with confirmation via . Treatment usually combines surgical removal (e.g., ) with using agents like , though median survival remains short at 4-6 months for visceral forms, highlighting the need for ongoing into targeted therapies shared between human and canine models due to their biological similarities.

General Overview

Definition and Classification

Hemangiosarcoma is a rare and aggressive malignant originating from endothelial cells that line blood vessels and lymphatic vessels. In humans, it is more commonly termed , while the designation hemangiosarcoma is frequently used in , particularly for cases in and . This tumor is characterized by its rapid proliferation, local , and high propensity for , distinguishing it from benign vascular lesions. As a subtype of , hemangiosarcoma falls under the broader category of in oncological classifications. The (WHO) Classification of and Bone Tumours (2020 edition) categorizes (hemangiosarcoma) as a malignant , emphasizing its endothelial differentiation through morphological and immunophenotypic features. Histologically, it exhibits variants including epithelioid (with rounded cells mimicking ), spindled (elongated cells forming slit-like spaces), and well-differentiated forms (resembling vascular channels with anastomosing sinusoids). These variants are identified via markers such as , , and factor VIII-related antigen, which confirm endothelial origin. Hemangiosarcoma must be differentiated from benign hemangioma, a non-malignant vascular proliferation that lacks invasive growth, atypia, and metastatic potential. While hemangiomas form well-circumscribed, encapsulated lesions with regular endothelial cells, hemangiosarcomas show pleomorphic, hyperchromatic nuclei, mitotic activity, and destructive infiltration into surrounding tissues. In veterinary contexts, such as canine cases, histological grading further classifies hemangiosarcomas into low, intermediate, and high grades based on criteria like cellular atypia and necrosis, aiding in prognosis assessment. Cutaneous forms are often more indolent and amenable to surgical excision compared to visceral variants, which arise in internal organs like the spleen or heart.

Epidemiology

Hemangiosarcoma, also known as in humans, is a rare accounting for 1-2% of all sarcomas. Its annual incidence is approximately 0.3 per 100,000 person-years, with over 1,300 new cases diagnosed in 2019 alone. In humans, the disease predominantly affects older adults, with a at of 71 years and a peak incidence in the 60- to 80-year-old group; there is a slight female predominance, with 54.5% of cases occurring in women. Global incidence remains low at around 0.1-0.3 per 100,000 across populations. In , hemangiosarcoma is far more prevalent in dogs than in other , representing up to 7% of all malignancies and serving as the most common malignant splenic tumor. The annual incidence risk in dogs is approximately 0.036% across all ages, rising to 0.074% in those aged 5 years and older. cases typically occur in middle-aged to older dogs, with a age of 10 years, and show a male predominance, particularly for visceral forms; breeds such as German Shepherds, Golden Retrievers, Labrador Retrievers, and Flat-Coated Retrievers are overrepresented. Hemangiosarcoma is rare in cats, comprising less than 1.5-2% of nonhematopoietic neoplasms, with only sporadic diagnoses in necropsy series (e.g., 18 cases in 3,145 necropsies over 11 years). cases most commonly affect middle-aged to older cats, with a mean age of 10 years and no clear breed or gender predisposition beyond a slight skew in reported series. In , hemangiosarcoma is sporadic and uncommon, with a reported of 0-0.7% in examined horses, primarily manifesting as cutaneous forms. Equine cases lack strong demographic trends but are noted in adult animals without specific age, gender, or breed overrepresentation in limited reports.

Pathogenesis

Etiology and Causes

Hemangiosarcoma primarily arises from the neoplastic transformation of endothelial cells that line blood vessels, leading to aggressive vascular tumors. In , the cellular is increasingly understood to involve hematopoietic precursors or bone marrow-derived progenitors that migrate to vascular niches and differentiate into endothelial-like cells, rather than solely mature endothelial cells. This is supported by studies showing hemangiosarcoma cells expressing markers of both endothelial and hematopoietic lineages, such as and CD34. Genetic mutations are central to the initiation of hemangiosarcoma, particularly in canine cases where somatic alterations in key tumor suppressor and pathways drive uncontrolled proliferation. Activating mutations in PIK3CA occur in approximately 45% of splenic hemangiosarcomas, often at hotspot residue 1047, leading to hyperactivation of the PI3K/AKT/mTOR signaling pathway. Inactivating mutations in TP53 are found in about 35% of cases, typically involving the and resulting in loss of tumor suppression. PTEN mutations, affecting around 10% of tumors, further dysregulate the PI3K pathway by removing inhibitory phosphate groups from PIP3. These genetic changes collectively promote endothelial cell survival and , initiating tumorigenesis. In humans, where the tumor is termed , certain environmental carcinogens have been established as triggers for hepatic forms, including exposure to (a historical ), arsenic (from medicinal or industrial sources), and (an industrial chemical). These agents induce sinusoidal cell and reticulin excess as precursors to , with cases showing similar histopathological progression to idiopathic ones. Despite these identified triggers, the of hemangiosarcoma remains idiopathic in the majority of cases across species, with no single initiating factor discernible in most instances. Rare viral associations have been noted in , where hemangiosarcoma can emerge alongside other tumors induced by feline sarcoma virus (FeSV), a recombinant derived from (FeLV) that requires FeLV for replication and promotes poorly differentiated sarcomas in young cats.

Risk Factors

Hemangiosarcoma, also known as in humans, is associated with several non-modifiable and modifiable risk factors that elevate susceptibility, particularly in specific subtypes. Prior , often administered for or other malignancies, significantly increases the risk of developing angiosarcoma, with tumors frequently arising in irradiated fields years later. Chronic lymphedema, especially post-mastectomy, can lead to Stewart-Treves syndrome, a rare variant occurring in approximately 0.45% of affected patients, characterized by angiosarcomatous changes in edematous tissues. Chemical exposures, such as in industrial settings, are strongly linked to hepatic angiosarcoma, with historical cohorts of exposed workers showing elevated incidence rates. (UV) radiation exposure is a key risk for cutaneous forms, particularly on sun-exposed areas like the head and neck. In humans, while no strong hereditary patterns exist for the majority of cases, rare familial clusters have been reported in association with genetic syndromes including neurofibromatosis type 1, Li-Fraumeni syndrome, Maffucci syndrome, Klippel-Trenaunay syndrome, and germline /2 mutations. In dogs, hemangiosarcoma exhibits clear genetic predispositions, with larger breeds such as , , and facing substantially higher risks due to polygenic inheritance identified through genome-wide association studies. For cutaneous variants, UV exposure plays a role, especially in dogs with lightly pigmented or short-coated skin, increasing susceptibility to dermal tumors on exposed areas. Advanced age is a universal non-modifiable factor across species, with most cases in dogs occurring in middle-aged to older individuals, typically over 6 years. Among other animals, horses with light-colored or unpigmented skin, such as Haflingers or Appaloosas, are predisposed to dermal hemangiosarcoma due to chronic UV exposure, which damages endothelial cells in sun-exposed regions like the periorbital area or limbs. remains a consistent in veterinary , including cats and horses, where tumors predominantly affect mature animals. No definitive protective factors against hemangiosarcoma have been established in humans or animals, though minimizing modifiable exposures like UV radiation or chemicals may mitigate risk in susceptible populations.

Pathophysiology

Tumor Biology

Hemangiosarcoma is a malignant tumor originating from endothelial cells lining blood vessels, characterized histologically by pleomorphic, immature endothelial cells that form irregular, slit-like vascular spaces often filled with blood and prone to hemorrhage and necrosis. These tumors exhibit varied morphologies, including capillary, cavernous, or solid patterns, with the neoplastic cells lining malformed vascular channels and expressing endothelial markers such as CD31 and von Willebrand factor. The hemorrhage-prone nature arises from the fragile, disorganized vascular structures, leading to frequent intratumoral bleeding and necrosis. The tumor's aggressive drives the formation of tortuous, dilated vascular channels filled with blood, promoting rapid growth and instability. This process involves upregulation of pro-angiogenic factors, resulting in chaotic vessel formation that supports the tumor's nutrient demands but contributes to its fragility. At the molecular level, hemangiosarcoma is driven by recurrent somatic mutations, including TP53 (in >70% of cases and frequent in ), PIK3CA, and NRAS in , and TP53, POT1, and in humans, which disrupt control, activate oncogenic signaling, and promote genomic instability. Dysregulation of (VEGF) signaling plays a central role, with hemangiosarcoma cells producing high levels of VEGF to stimulate autocrine and paracrine . Genetic studies in models demonstrate that even partial loss of endothelial-derived VEGF significantly reduces tumor incidence, highlighting its essential role in initiation and progression. Hypoxia-inducible factor 1-alpha (HIF-1α) further contributes by responding to the hypoxic tumor environment, enhancing VEGF expression and other genes that promote vascularization and survival under low-oxygen conditions. Due to its vascular origin, hemangiosarcoma exhibits high metastatic potential through early hematogenous spread, allowing tumor cells to disseminate via the bloodstream. Common metastatic sites include the lungs and liver, where emboli of neoplastic endothelial cells lodge and form secondary tumors, often present at in over 60% of cases. This rapid dissemination is facilitated by the tumor's ability to invade vessel walls and exploit the . The in hemangiosarcoma is enriched with inflammatory cells and factors that support growth and enable immune evasion. Proinflammatory cytokines such as interleukin-8 (IL-8) and like recruit immune cells, creating a permissive niche that enhances tumor , , and survival while polarizing macrophages toward an immunosuppressive M2 . Regulatory T cells (Tregs) accumulate in the microenvironment, suppressing antitumor immunity through checkpoint molecules like CTLA-4, thereby facilitating progression and . This inflammatory milieu also intersects with angiogenic pathways, amplifying the tumor's aggressive behavior.

Common Sites of Origin

Hemangiosarcoma, a malignant tumor arising from vascular endothelial cells, most commonly originates in visceral organs in dogs, with the spleen accounting for 50-65% of cases. The right atrium of the heart represents another primary visceral site in dogs, often leading to pericardial effusion and acute clinical deterioration due to its propensity for rupture. In humans, cardiac angiosarcoma similarly favors the right atrium, comprising a significant portion of rare primary heart tumors. The liver serves as a frequent visceral site, particularly in humans following exposure to chemicals such as , where hepatic develops in association with industrial toxins. In , liver involvement often occurs as a or , though less dominant than splenic origins. Cutaneous and subcutaneous forms arise in sun-exposed skin areas, linked to ; these account for approximately 13% of hemangiosarcomas in , typically in lightly pigmented breeds. In humans, cutaneous predominates, affecting about 60% of cases, most often on the head and neck in elderly individuals. Less common sites include the retroperitoneum, bone (such as the radius), and brain, where tumors exhibit similar vascular origins but rarer incidence across species. Multicentric disease, involving simultaneous primaries at multiple sites like spleen and heart, complicates staging and occurs in up to 25% of canine cases, reflecting the tumor's propensity for widespread endothelial involvement. Cardiac tumors demonstrate heightened aggressiveness, frequently causing life-threatening hemorrhagic events compared to more indolent cutaneous variants.

Clinical Presentation

Signs and Symptoms

Hemangiosarcoma presents with nonspecific clinical signs that vary by species, tumor location, and whether it is cutaneous or visceral. Due to its vascular origin, the tumor can cause hemorrhage, leading to , weakness, lethargy, pallor of mucous membranes, anorexia, , and . In visceral forms, particularly common in dogs, acute manifestations often result from tumor rupture, causing sudden collapse, due to (especially splenic origin), and . Cardiac involvement may lead to arrhythmias, with , dyspnea, and syncope. Metastatic spread can worsen these through additional hemorrhage or organ dysfunction. Cutaneous forms, more prevalent in humans and horses, typically manifest as bruise-like lesions, red to purple nodules, or raised masses on that may ulcerate and bleed intermittently, resembling hematomas. In humans, visceral sites like or liver may cause localized , swelling, , or . Systemic effects such as and coagulopathies can occur across forms. Early-stage disease is often and found incidentally during examinations or .

Species Variations

Hemangiosarcoma, also known as in humans, exhibits variations in clinical presentation across species, influenced by predominant tumor locations. In humans, it most frequently manifests as cutaneous lesions on the , face, or other sun-exposed areas, presenting as bruise-like or red nodules, plaques, or ulcers that enlarge gradually and may bleed intermittently. Visceral presentations in , liver, or are less common and associated with risk factors like or chemicals, causing localized , swelling, or systemic symptoms like and . In dogs, it predominantly affects visceral organs, with the majority of cases originating in the spleen or right atrium of the heart, leading to rapid metastasis and high risk of rupture causing acute internal hemorrhage. Signs include sudden collapse, profound weakness, pale mucous membranes, abdominal distension, and rapid breathing. Cutaneous forms are less common and generally have a better prognosis. In , common sites include cutaneous areas and the , with presentations such as masses, , anorexia, , , or abdominal swelling. The disease has high metastatic potential and poor prognosis, with risks of internal bleeding and collapse similar to dogs. In horses, it primarily arises in dermal or conjunctival sites, often in lightly pigmented areas due to UV , manifesting as raised red-to-black nodules or ulcerative lesions on the , eyelids, or . Signs are usually localized (e.g., ocular discharge, swelling, lameness), with visceral forms rare and causing nonspecific symptoms like or dyspnea. Detection often occurs incidentally in animals during routine exams, while in humans, cutaneous or visceral symptoms prompt evaluation.

Diagnosis

Diagnostic Methods

Diagnosis of hemangiosarcoma typically involves a combination of clinical evaluation, imaging, laboratory tests, and histopathological confirmation to identify the vascular origin of the tumor and assess its extent. In dogs, initial suspicion often arises from nonspecific signs like weakness or abdominal distension, prompting targeted diagnostics based on common sites such as the spleen or heart. In humans (where termed angiosarcoma), presentation may include skin lesions or organ-specific symptoms, with diagnosis emphasizing biopsy and imaging for sites like skin, breast, or liver. Imaging plays a central role in detecting primary tumors and metastases. In dogs, abdominal is commonly used to identify splenic or hepatic masses, appearing as heterogeneous, hypoechoic lesions with or mixed , and to detect peritoneal . For cardiac involvement, reveals right atrial masses and associated , aiding in preoperative planning. Advanced cross-sectional imaging like computed (CT) or (MRI) enhances by detecting pulmonary or distant metastases; CT shows heterogeneous contrast enhancement in vascular phases, while MRI delineates soft tissue invasion with intermediate T1 and hyperintense T2 signals. In humans, similar imaging is used, with (PET)-CT often employed for due to its for metastases. Laboratory findings often support the diagnosis through evidence of hemorrhage and . In dogs, regenerative or nonregenerative is frequent due to , accompanied by in approximately 70% of cases, schistocytes, and acanthocytes on blood smears. Coagulation panels may reveal (DIC) risks, including prolonged , activated , hypofibrinogenemia, and elevated fibrin degradation products, reflecting microangiopathic damage. with a left shift can also occur. In humans, lab findings are less uniformly hemorrhagic but may include or elevated liver enzymes if hepatic involvement. Cytological examination via (FNA) is a presurgical screening tool but is often inconclusive due to hemodilution and hemorrhage, potentially mimicking hemangiomas. In humans, core biopsy is preferred over FNA for better sampling. Definitive requires histopathology from incisional or excisional biopsies, revealing infiltrative vascular channels lined by malignant endothelial cells with hemorrhage and necrosis. Immunohistochemistry confirms endothelial origin using markers such as and Factor VIII-related antigen (), which highlight vascular structures and differentiate from other sarcomas; in humans, additional markers like ERG and Fli-1 may be used. Staging employs adapted systems like the three-stage model (I: localized, II: ruptured or invading locally, III: metastatic), incorporating tumor size, involvement, and distant spread assessed via and sometimes evaluation. This guides prognosis and therapy, with complete including thoracic radiographs or for pulmonary assessment. Human follows guidelines, often using TNM with PET- for M stage. Advanced techniques include to detect endothelial progenitor markers like , , and c-kit in circulating cells, potentially identifying early disease or primitive origins in research settings, though not routine clinically. (CEUS) and further characterize lesions by vascular patterns and stiffness, with shear wave velocities over 2.6 m/s suggesting .

Differential Diagnosis

Hemangiosarcoma, particularly in its visceral forms affecting the spleen, heart, or liver, can mimic several other conditions due to shared features such as hemorrhage, vascular involvement, or mass effects. In dogs, the most common differentials for a splenic mass include benign vascular lesions like hemangioma, which is distinguished by its lack of metastasis, well-circumscribed borders on imaging, and absence of cellular atypia on histopathology. Hematomas, non-neoplastic collections of blood often resulting from trauma or coagulopathies, present similarly with hemoabdomen but lack neoplastic cells on cytology or biopsy and typically resolve without progression. Lymphoma, a hematologic malignancy, may involve the spleen diffusely or as nodules and is differentiated by lymphoid markers such as CD3 or CD79a on immunohistochemistry, contrasting with the endothelial markers (e.g., CD31, CD34) positive in hemangiosarcoma. Other malignant tumors, such as originating from , can be distinguished histologically by positive staining for smooth muscle actin and desmin, while often shows pigmentation and S-100 protein expression. Non-neoplastic mimics like infectious abscesses are identified through cytology revealing inflammatory cells, bacteria, or fungi, often accompanied by systemic signs such as fever, and coagulopathies (e.g., ) may cause spontaneous bleeding without a discrete mass, confirmed by coagulation profiles showing prolonged or . In humans, where the condition is termed , key differentials include benign hemangiomas (lacking infiltrative growth and atypia), Kaposi sarcoma (associated with HHV-8 and positive for that viral marker), and (intermediate grade with less pleomorphism), primarily differentiated via and for vascular endothelial markers. Distinction from these mimics relies on imaging characteristics, such as vascular flow voids on or contrast enhancement patterns indicating hypervascularity in hemangiosarcoma, alongside demonstrating malignant endothelial cells lining irregular vascular spaces. The absence of , mitotic figures, or invasion in benign entities like further aids differentiation. However, acute hemorrhage frequently obscures tumor features in both species, complicating preoperative assessment and often necessitating for definitive diagnosis in dogs, as yields low sensitivity due to sampling errors and bleeding risks.

Treatment

Surgical Options

Surgical intervention serves as the primary treatment modality for hemangiosarcoma, aiming to achieve complete tumor resection when feasible, though its aggressive nature and often limit curative outcomes. For splenic hemangiosarcoma, particularly prevalent in dogs, is the standard procedure, involving complete removal of the to address the tumor and prevent life-threatening rupture. This approach is often palliative in cases of tumor rupture, stabilizing the patient by halting acute hemorrhage and allowing time for further management. Cardiac hemangiosarcoma presents significant surgical challenges due to the tumor's location within or near the heart, frequently requiring adjunctive pericardectomy to relieve and prevent . Tumor resection in the right atrium or other cardiac sites may be attempted under , but such procedures are technically demanding and carry high risks; in humans, they are rarely curative given the tumor's propensity for early . For cutaneous hemangiosarcoma, with 1-2 cm lateral margins and deep extension to the fascial plane offers the potential for cure if clean margins are achieved and no distant spread is present. In cases of unresectable hemangiosarcoma, such as advanced hepatic or multifocal , debulking surgery may be performed to reduce tumor burden and alleviate symptoms like vascular obstruction or compression, though it does not address microscopic . Common complications across these procedures include intraoperative hemorrhage from the tumor's fragile vascular structure and postoperative cardiac arrhythmias, particularly following or pericardial manipulation. For incomplete resections, therapies are often recommended to target residual .

Adjuvant Therapies

Adjuvant therapies for hemangiosarcoma aim to complement surgical intervention by targeting microscopic , reducing recurrence, or providing palliation when is incomplete or not feasible. In , particularly for canine cases, doxorubicin-based chemotherapy protocols are the cornerstone of treatment following splenectomy for splenic hemangiosarcoma. Single-agent doxorubicin administered every 2-3 weeks for 4-5 cycles has been shown to extend median survival from approximately 1-3 months with alone to 5-7 months. Combination protocols, such as vincristine, doxorubicin, and cyclophosphamide (VAC), offer similar benefits without significantly improving outcomes over single-agent therapy but may be used in cases of advanced . In human , which shares histological similarities with hemangiosarcoma, doxorubicin-based regimens are also employed post-resection, though evidence is limited due to rarity, with response rates around 20-30% in metastatic settings. Radiation therapy serves primarily as a palliative modality for hemangiosarcoma, particularly in cutaneous, subcutaneous, or unresectable visceral tumors where surgical margins are incomplete. In dogs with nonsplenic hemangiosarcoma, palliative protocols delivering 20-30 in 3-5 fractions achieve subjective tumor reduction in up to 70% of cases, with median survival times of about 3 months and minimal due to the vascular nature limiting curative intent. For cardiac hemangiosarcoma in dogs, hypofractionated radiation (e.g., 12 in a single fraction) has demonstrated feasibility and short-term stabilization in pilot studies, though long-term control remains challenging owing to the tumor's and metastatic propensity. In humans, stereotactic body radiotherapy is occasionally used adjuvantly for localized , providing local control rates of 50-70% in small series, but systemic progression often predominates. Targeted therapies, particularly anti-angiogenic agents, represent an emerging adjuvant strategy exploiting hemangiosarcoma's vascular origin. inhibitors like , which inhibit VEGF and PDGF receptors, have shown promise in human as second-line therapy, with phase II trials reporting disease control rates of 50% at 3 months, especially in cutaneous subtypes, and median of 3-4 months. In preclinical models, similar multi-kinase inhibitors demonstrate anti-angiogenic effects, though clinical adoption remains investigational. These agents are typically reserved for cases refractory to , with monitoring for and essential. Immunotherapy approaches are largely experimental for hemangiosarcoma, focusing on and checkpoint inhibitors to harness antitumor immunity. In trials, such as the extracellular (eVim)-targeted combined with post-surgery have improved outcomes, with a 2025 phase I/II study showing a median survival of 235 days and 1-year survival rate of 44% in dogs with visceral hemangiosarcoma, compared to 136 days and 14% with alone, without added toxicity. Other approaches, including the EVM , have reported 1-year survival rates of 35.7% in settings. For human , checkpoint inhibitors like are under evaluation in trials, yielding objective responses in 20-40% of vascular sarcomas with high mutational burden. Ongoing veterinary trials, including multivalent for hemangiosarcoma, aim to validate these as adjuncts to standard care. Supportive therapies are integral to adjuvant management, addressing complications like and hemorrhage from tumor rupture. In dogs, or packed transfusions are commonly required pre- or post-surgery for severe (hematocrit <20%), stabilizing patients and enabling tolerance, with transfusion rates up to 50% in splenic cases. with opioids or NSAIDs, alongside fluid therapy, enhances during multimodal treatment. In humans, similar supportive measures, including erythropoietin-stimulating agents for -induced , support adjuvant regimens without altering core outcomes.

Prognosis

Survival Rates

Hemangiosarcoma, also known as in humans, exhibits highly variable survival outcomes depending on the primary site and disease stage. In humans, localized cutaneous forms have reported 5-year survival rates of approximately 30-50%, reflecting better outcomes when tumors are confined to and amenable to complete surgical resection. In contrast, metastatic visceral hemangiosarcomas, often involving organs such as the liver or , carry a dismal with 5-year survival rates of approximately 10-20% and median overall survival of 6-16 months, even with . In , the most common species affected, untreated hemangiosarcoma typically results in survival times of 1-3 months due to rapid progression and rupture-related complications. Surgical intervention alone, such as for splenic tumors, extends survival to 4-6 months, while adjunctive (e.g., doxorubicin-based protocols) can achieve up to 6-12 months in select cases, though 1-year rates are approximately 10-20% in reported cohorts. Cutaneous variants generally confer longer , with times exceeding 2 years for early-stage, actinic forms following excision. For , survival is more favorable in cutaneous hemangiosarcoma compared to other forms, where complete surgical excision can yield median times of approximately 9-12 months overall, with longer outcomes possible for superficial lesions based on studies through 2023. Visceral forms, however, are aggressive, with median of approximately 2-3 months post-surgery and limited extension from . In horses, isolated cutaneous or ocular hemangiosarcomas respond well to surgical excision, often resulting in cure rates exceeding 80% and long-term (e.g., over 2 years in small cohorts), provided margins are clean and no occurs. Disseminated visceral , though rarer, portends a poor outcome similar to other species. Across species, is strongly influenced by the stage at —early detection markedly improves —and the anatomic site, with cutaneous presentations consistently outperforming visceral ones due to lower metastatic potential. data are based on studies up to 2023, with no major changes reported as of 2025.

Prognostic Factors

Prognostic factors for hemangiosarcoma encompass a range of tumor, , and biological characteristics that influence disease progression and outcomes, with variations observed across but particularly well-studied in . Tumor stage at is a primary determinant, where localized disease (stage I) confers a more favorable course compared to metastatic involvement (stage III), as the presence of distant spread significantly shortens due to widespread often detected in over 75% of cases at necropsy. Similarly, the anatomic site of the tumor plays a critical role; cutaneous hemangiosarcomas generally exhibit better prognoses owing to their superficial nature and lower metastatic potential, whereas visceral sites such as cardiac or splenic locations are associated with aggressive and poorer outcomes, largely attributable to the high of rupture and internal hemorrhage. Histological further refines , with high-grade tumors demonstrating more rapid progression and reduced survival relative to low-grade variants, reflecting increased cellular and mitotic activity that drive invasion and . Among patient-related factors, age shows inconsistent impact in , typically affecting middle-aged to geriatric individuals without a strong independent prognostic effect, though advanced age beyond 70 years correlates with worse outcomes in cases. Performance status, including the presence of or , adversely affects in visceral forms, signaling systemic compromise and advanced disease burden. , particularly pericardial in cardiac hemangiosarcoma, indicates advanced involvement and is linked to diminished survival, as it often accompanies and hemodynamic instability. Arrhythmias, commonly seen in cardiac presentations, similarly portend a guarded outlook by reflecting tumor-induced myocardial disruption and complicating clinical management. Response markers provide additional prognostic insight through histopathological evaluation. The Ki-67 proliferation index, a measure of cellular replication, is elevated in aggressive hemangiosarcomas and serves as an independent predictor of shorter survival, with indices exceeding 56% in splenic cases associated with poorer outcomes. Vascular invasion identified on heightens the risk of , particularly in subcutaneous or dermal tumors, thereby worsening by facilitating early systemic spread. These factors collectively guide clinical , emphasizing the need for thorough and histopathological assessment to tailor expectations.

Occurrence in Humans

Incidence and Demographics

Hemangiosarcoma, also known as in humans, is a rare accounting for approximately -2% of all sarcomas, with an estimated annual incidence of about ,300 cases as of 2019. The age-adjusted incidence rate has been reported at around 3 cases per ,000,000 person-years, reflecting a notable increase from earlier decades. Demographically, angiosarcoma predominantly affects older adults, with a median age at diagnosis of 71 years and the majority of cases occurring in individuals aged 60 years or older. It shows a slight female predominance overall (approximately 54.5% of cases), though this varies by subtype; for instance, cutaneous forms exhibit a male-to-female ratio of about 2:1, while angiosarcomas are nearly exclusive to women. Non-Hispanic individuals represent the largest racial group affected, comprising roughly 75% of cases in population-based analyses. In terms of site distribution, cutaneous angiosarcomas are the most common, accounting for about 60% of cases and frequently involving the head and neck region. Other primary sites include deep soft tissues (approximately 36%), breast (13-22%), visceral organs such as the liver and heart (17%), and bone (3%). The incidence of angiosarcoma has risen over time, doubling in the US from 657 cases in 2001 to 1,312 in 2019, with an annual increase in the age-adjusted rate of 1.6%. This trend is partly attributed to a growing proportion of secondary cases linked to prior for other cancers, particularly . Globally, angiosarcoma remains rare with an incidence of 1-3 cases per million population annually, but rates appear higher in industrialized regions due to associations with occupational chemical exposures, such as in liver angiosarcomas.

Human-Specific Management

Management of angiosarcoma in humans requires a multidisciplinary approach, typically involving sarcoma reference centers where dedicated teams of pathologists, radiologists, surgeons, medical oncologists, and radiation oncologists collaborate to tailor treatment plans. This coordinated care is essential due to the tumor's aggressive nature and variable presentations, ensuring comprehensive evaluation and individualized strategies. For large or locally advanced tumors, neoadjuvant chemotherapy is often employed to shrink the lesion, facilitating subsequent surgical resection and improving margin status. Regimens commonly include anthracyclines or taxanes, administered prior to surgery to enhance resectability in cases where upfront excision might otherwise be challenging. In advanced or metastatic disease, targeted therapies play a key role; weekly paclitaxel has emerged as a standard option, demonstrating response rates around 40-50% in pretreated patients. For subsets expressing PD-L1 or with microsatellite instability-high features, anti-PD-1 inhibitors such as pembrolizumab have shown durable responses in select cases, particularly within clinical trial settings. Radiation therapy is integral, often delivered postoperatively to address close or positive margins, reducing local recurrence risk in resectable cases. For inoperable tumors, definitive radiation serves as a primary modality, sometimes combined with chemotherapy to achieve local control. Enrollment in clinical trials is strongly encouraged, especially for novel anti-angiogenic agents like bevacizumab, which targets vascular endothelial growth factor and has demonstrated efficacy in metastatic angiosarcoma with response rates up to 25% in phase II studies. Palliative care focuses on symptom management and in metastatic settings, where systemic therapies aim to prolong survival; median overall survival in this context ranges from 8 to 12 months with current approaches.

Occurrence in Dogs

Prevalence and Breed Predispositions

Hemangiosarcoma accounts for approximately 5-7% of all tumors diagnosed in , making it one of the most common malignancies encountered in veterinary . It represents about 5% of all cancers overall and is frequently identified during necropsy, occurring in 0.3% to 2% of examined cases. While exact incidence rates vary by study, population-based analyses indicate an annual incidence of around 0.035% (95% : 0.03-0.038%) in aged 5 years or older in the as of 2019. Certain breeds exhibit significantly elevated risks for developing hemangiosarcoma, highlighting a particularly in purebred populations. German Shepherds face the highest risk, with an of 6.14 (95% CI: 4.73–7.98) compared to reference breeds. Golden Retrievers and Labrador Retrievers also show increased susceptibility, with odds ratios of 2.05 (95% CI: 1.33–3.17) and 1.42 (95% CI: 1.11–1.83), respectively. This is evident in pedigree dogs, where breed-specific genetic factors contribute to higher incidence rates, though environmental influences may play a minor role. Geographic variations in prevalence appear minimal, with similar patterns observed across , , and other regions without strong regional disparities. The condition predominantly affects older dogs, with a median age at diagnosis of 9 to 10 years, though cases can occur in younger animals. There is a slight male bias, with neutered males showing a modestly higher risk (odds ratio 1.49, 95% CI: 1.17–1.90) compared to entire females. Among diagnosed cases, visceral forms dominate, comprising the majority—estimated at over 70%—and most commonly involving the spleen or heart at the time of presentation.

Canine-Specific Clinical Features

Hemangiosarcoma in dogs often presents with acute and life-threatening clinical features due to its vascular nature, distinguishing it from more indolent tumors. A significant is , with studies reporting that 25% to 65% of cases involve splenic rupture leading to massive internal hemorrhage and . This rupture can occur without prior warning, causing rapid collapse and fatality if untreated. When involving the heart, particularly the right atrium, hemangiosarcoma frequently causes pericardial effusion, leading to specific cardiac signs such as syncope and muffled heart sounds on auscultation. These symptoms arise from cardiac tamponade, where accumulated blood in the pericardial sac compresses the heart, impairing cardiac output and resulting in episodes of fainting, especially during exertion. Cutaneous hemangiosarcoma in typically manifests as rapidly growing, fragile lesions on , often in hypopigmented or lightly haired areas, which may reach 5-10 cm in diameter within weeks to months. These tumors appear as red to black, raised masses that can and bleed easily due to their vascular composition. Early is a hallmark, with approximately 80% of harboring micrometastases at the time of , frequently remaining and undetected by routine . This widespread dissemination contributes to the aggressive course, even in apparently localized disease. Behavioral changes in affected often include acute weakness following exercise, accompanied by pale mucous membranes indicative of ongoing hemorrhage. These signs reflect the tumor's propensity for vascular leakage, leading to and reduced oxygen delivery to tissues.

Occurrence in Other Animals

In Cats

Hemangiosarcoma is a rare in cats, accounting for less than 1.5% to 2% of all nonhematopoietic neoplasms reported in pathology registries. It most commonly arises in (cutaneous or dermal form) or viscera, particularly the , with the overall incidence in cats being substantially lower than in . Unlike in canines, no strong breed predispositions have been identified, though the condition predominantly affects older cats with a mean age of approximately 10 years (range 4–19 years). Cutaneous hemangiosarcoma in typically presents as indolent, non-ulcerative nodules on the head, pinnae, paws, or trunk, often discovered incidentally during grooming or examination. In contrast, visceral forms are more aggressive and manifest with systemic signs such as anorexia, , , collapse, or respiratory distress due to internal hemorrhage or organ involvement, commonly affecting the , liver, or intestines. occurs less frequently in compared to dogs, with evidence of spread in only about 38% of staged cases, primarily to the lungs or liver. Prognosis varies significantly by location and treatment. Cutaneous lesions often respond well to wide surgical excision, particularly when complete margins are achieved, potentially offering a curative outcome with median survival exceeding 283 days and no tumor-related deaths in some cohorts. Visceral hemangiosarcoma, however, carries a grave outlook, with many cats euthanized shortly after diagnosis due to severe clinical signs and anemia; for those undergoing splenectomy or supportive care, median survival is around 77 days. Adjuvant therapies like chemotherapy are infrequently used but may extend survival in select cases.

In Horses

Hemangiosarcoma is an uncommon in horses, primarily presenting as cutaneous or tumors arising from vascular endothelial cells in sun-exposed areas. These tumors most frequently affect the third eyelid, bulbar , and lightly pigmented , such as the ventral , in with pale or dilute colors living in sunny climates. Chronic light exposure is a key , often associated with elastosis in affected tissues. Internal hemangiosarcomas are rare in horses and typically involve the spleen or skeletal muscle, manifesting clinically as acute colic from splenic rupture and hemorrhage or lameness due to intramuscular masses. The disease predominantly occurs in middle-aged to older horses, with reported mean ages ranging from 12 to 16 years across cases, and no sex bias has been identified. Thoroughbreds may be overrepresented, though no definitive breed predisposition exists. Cutaneous and conjunctival forms often appear as slow-growing, exophytic, hyperemic vascular masses, with ulceration possible in advanced skin lesions; metastasis is uncommon in these localized presentations. In contrast, internal cases frequently disseminate rapidly to multiple organs, including the lungs, heart, and kidneys, leading to systemic signs like dyspnea, epistaxis, or subcutaneous swelling. Surgical excision, including conjunctivectomy, keratectomy, or enucleation for ocular involvement, is the primary for localized tumors and is often curative, with many surviving over 2 years post-surgery without recurrence. Adjunctive therapies like may be used, but their efficacy is not well-established. For disseminated internal disease, is guarded to poor, with supportive care such as fluid and transfusions providing only palliative relief, as is common within weeks of .